Comparison of Pharmacokinetics of Dapsone in Male Sprague Dawley Rats Following Retro Orbital, Jugular Vein and Saphenous Vein Blood Sampling

Subrahmanyam Vangala

doi:10.15226/2374-6866/2/1/00122

Abstract

Pharmacokinetic (PK) studies play an important role in identifying lead compounds for further development. Typically rats are used for PK screening of New Chemical Entities (NCEs) as the compound requirements are minimal (<10 mg), multiple blood sampling (up to 10 samples) can be performed from the same animal and in small volumes (5-25μL) for sample analysis. Blood sampling site is critical in obtaining multiple blood samples of good quality and in small volumes with minimal stress to animals. However, it is not known whether PK parameters can be influenced by sampling site. Thus, in this study, we evaluated the effect of different blood sampling sites like retro-orbital plexus, jugular vein and saphenous vein on PK parameters of Dapsone. Dapsone was administered both orally and intravenously at a dose of 12 mg/kg to a group of 4 male Sprague Dawley rats and blood samples were collected up to 24 h. Samples were analyzed by LC/MS/MS and PK parameters were calculated. With all the sampling techniques, PK parameters like clearance, volume of distribution, half-life and bioavailability were similar. Due to the control on the blood volume withdrawn at each time point, quick sampling with minimal hemolysis and minimal animal handling stress during sampling, Jugular Vein (JV) or Saphenous Vein (SV) sampled rats can be used for PK studies. Further for saphenous sampling no pre-study preparation like cannulation is required before dosing the animals therefore sampling of rats through saphenous vein is recommended for pharmacokinetic and toxicokinetic studies. To summarize, SV sampling reduce the number of animals in different Pharmacokinetic (PK) (mouse) and Toxicokinetic (TK) (mouse and rat) studies by using serial draws, offers reduction and refinement over the othersampling techniques with minimal preparation upfront and with a potential to replace them.

Highlights

Pharmacokinetic (PK) studies play a vital role in selecting a lead compound for further development
Compared to assessed sampling techniques, we found saphenous vein sampling to have the following advantages
Animals are not catheterized, blood volume drawn can be controlled without hemolysis of samples and no upfront preparation is required to initiate the study at short notice

Summary

Introduction

Pharmacokinetic (PK) studies play a vital role in selecting a lead compound for further development. Rats are the preferred rodent species for assessing PK behavior of new chemical entities (NCEs).Typically during drug discovery phase limited compound availability can be a hurdle to conduct detailed and robust pharmacokinetic studies with large number of animals. The recent advances in micro sampling techniques, highly sensitive LC-MS methods made it possible to conduct robust and detailed PK studies during drug discovery, with limited number of animals. In PK studies, following administration of the compound, serial blood samples (usually 9-10 time points) are preferred, as they give a more robust concentration versus time profile within the same animal. These samples are analyzed for the parent or metabolite using a suitable analytical technique. Based on the PK and other druggable properties, the NCEs are rank ordered and decisions are made for further development of the NCE

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